The worldwide obesity epidemic, and an array of obesity-related disorders, particularly diabetes, fatty liver and cardiovascular disease, have become a major public health threat in the 21st century. Yet the molecular and pathological mechanisms by which obesity induces metabolic disorders remain incompletely understood hampering the development of effective therapies against these debilitating diseases. In recent years, long non-coding RNAs (lncRNAs) have emerged as a key component of human genome and bioinformatics analyses have implicated these non-coding transcripts in energy and nutrient metabolism. We have screened and identified a significant number of lncRNAs that are directly involved in metabolic regulation. We demonstrated that lncRNA expressions are regulated by key nutrient factors and cellular nutrient statuses, and numerous lncRNAs modulate signaling and metabolic pathways to control energy homeostasis. We are currently using transgenic over-expression and knockdown in mice to define the physiological functions of selected lncRNAs in systemic glucose and lipid metabolism. In addition, we are also pursuing the pathological role of lncRNAs in obese and diabetic mice and corroborate our findings using patient samples.